Norbert Suttorp

Diese Studie mit Christian Karagiannidis als Erst- und Reinhard Busse als Letztautor im Lancet [1] ist etwas ganz Besonderes: Daten zu 1 Million beatmeten Patienten in Deutschland über 4 Jahre (2019–2022). Das Vorliegen eines kompletten Datensatzes (ausgenommen verlegte beatmete Patienten) ist einmalig und mir war sofort klar: Das wird viele Diskussionen und viel Nachdenken über unser Gesundheitssystem sowohl in der Medizin als auch in der breiten Öffentlichkeit auslösen. Die Ergebnisse muss man erstmal „sacken“ lassen: Die Rate an Beatmungen pro 100.000 Einwohner beginnt bei jüngeren Patienten bei 110 und endet mit 1275 bei Patienten > 80 Jahre. Die Daten sind weiter aufgeschlüsselt nach Beatmungsart (nicht-invasiv, invasiv, ECMO) und Hauptdiagnose und Komorbidität sind jeweils erfasst. Die durchschnittliche Mortalität betrug 43 % (28 % bei den Jüngeren und 59 % bei den Patienten > 80 Jahre). Durchschnittlich 11 % aller Verstorbenen der deutschen Gesamtbevölkerung sterben am Beatmungsgerät. Die Kosten für Beatmung pro Jahr in Deutschland betragen ca. 6 Milliarden Euro. Ich war wirklich überrascht, wie viele Personen hierzulande insgesamt beatmet werden und wie viele > 80-Jährige beatmet werden. Unter Beatmung verstirbt etwa jeder Zehnte aller Verstorbenen der deutschen Gesamtbevölkerung, bei Erwachsenen im Alter unter 60 Jahren fast jeder Fünfte. Es gibt natürlich Indikationen, auch Patienten > 80 Jahre zu beatmen, aber die sehr hohe Zahl dieser Patienten macht nachdenklich. Eine solch hohe Rate an beatmeten älteren Patienten gibt es nur noch in den USA. Sie ist halb so hoch in Kanada und in England beträgt sie nur ca. 1/5 [2]! Die durchschnittliche Sterblichkeit, die hier als Real-World-Daten vorliegt, ist sehr hoch und viel höher, als sie uns aus kontrollierten Studien bekannt ist. Folgende Gedanken ergeben sich unmittelbar: Applaus den Autoren zu dieser augenöffnenden Studie. Nur eine gute Studie eröffnet die Möglichkeit vieler neuer Fragen. Die Studie muss die Gesellschaft im Allgemeinen und die Medizin im Besonderen beschäftigen. Sie ist auch ein sehr wichtiges Stück Information angesichts der angestrebten Krankenhausreform, deren dezidiertes Ziel es ist, mehr Qualität in die Krankenversorgung zu bringen. Article published online: 12 June 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia.

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8 ^–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PROGRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10⁻²⁰), at 17q21.32 (p = 1.51 × 10⁻⁹) and at 10p12.1 (p = 2.76 × 10⁻⁹) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10⁻⁹), and at 9q34.12 for IL-10 (p = 4.52 × 10⁻⁸). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms.

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC₅₀of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, in order to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. Methods: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. Results: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional and health-related quality of life assessments at discharge and during follow-up. We developed a scalable dataset to ( i ) suit national standards of care ( ii ) facilitate comprehensive data collection in medical care facilities with varying resources and ( iii ) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. Conclusion: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents.

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide ¹ . Clinical manifestations of Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death ² , yet the underlying mechanisms for this high variability are still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4 ⁺ T cell responses correlated with positive outcomes ^3,4 , whereas T cell immune responses to SARS-CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4 ⁺ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4 ⁺ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower frequencies. Strikingly, S-reactive CD4 ⁺ T cells in COVID-19 patients equally targeted N-terminal and C-terminal epitopes of S whereas in HD S-reactive CD4 ⁺ T cells reacted almost exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike glycoprotein of human endemic “common cold” coronaviruses (hCoVs), and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4 ⁺ T cells in HD, S-reactive CD4 ⁺ T cells from COVID-19 patients co-expressed CD38 and HLA-DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology for COVID-19. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.